1. Field of the Invention
This invention relates to oncology and medicine, and more particularly to treatment of tamoxifen resistant cancers. In particular, MUC1 peptides derived from a particular region of the MUC1 cytoplasmic domain have been shown to inhibit MUC1 oligomerization and nuclear translocation, causing inhibition and even death of MUC1-expressing tumor cells, and these can be used advantageously in combination with ER-overexpressing cancers, as well as those that have developed resistant to ER-targeted therapies.
2. Related Art
The estrogen receptor α (ERα) signaling pathway contributes to the development and progression of human breast cancers. Over 70% of all breast cancers express ERα with a somewhat higher frequency in tumors from postmenopausal women (Osborne et al., 2011). Endocrine therapy of patients with ER+ breast cancer has included (i) blocking estrogen binding with selective ER modulators, such as tamoxifen, (ii) decreasing ER expression with fulvestrant, and (iii) inhibiting estrogen synthesis with aromatase inhibitors. These endocrine therapies have had a major impact on the natural history of hormone-dependent breast cancer; however, their effectiveness is often limited by intrinsic or acquired resistance (Osborne et al., 2011 and Musgrove et at., 2009). For example, adjuvant therapy of ER+ breast cancers with tamoxifen is associated with recurrent disease in about one-third of patients (Musgrove et al., 2009). One mechanism of acquired tamoxifen resistance is the downregulation of ERα expression, although this response has been observed in only 15-20% of breast cancers (Gutierrez et al., 2005). Tamoxifen resistance has also been linked to cross-talk between ERα and receptor tyrosine kinases (RTKs), specifically epidermal growth factor receptor (EGFR), the epidermal growth factor receptor 2 (HER2/ERBB2) and the insulin-like growth factor receptor (IGF1-R) (Osborne et al., 2011; Musgrove et at., 2009). In this context, amplification and overexpression of HER2 has been associated with endocrine resistance (De Laurentiis et al., 2005, Ellis et al., 2006, Arpino et al., 2008). However, only about 10% of ER+ breast cancers overexpress HER2, indicating that additional mechanisms confer tamoxifen resistance in the majority of these tumors. Other work has shown that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway confers resistance to endocrine therapy through both direct and indirect ERα interactions (Miller et al., 2011). Accordingly, PI3K pathway inhibitors are being evaluated for the treatment of patients with tamoxifen-resistant ER+ breast cancer (Miller et al., 2011a). Nonetheless, new therapeutic targets are needed for the treatment of tamoxifen-resistant disease.
The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in about 90% of human breast cancers (Kufe, 2012). The two MUC1 subunits are generated by autocleavage of a single polypeptide and, in turn, form a stable non-covalent complex (Kufe, 2012; 2009). The MUC1 N-terminal subunit (MUC1-N) is the heavily glycosylated mucin component of the heterodimer. MUC1-N is positioned extracellularly in a complex at the cell membrane with the MUC1 C-terminal (MUC1-C) transmembrane subunit (Kufe, 2009). MUC1-C functions as an oncoprotein by interacting with RTKs, such as EGFR and HER2, at the breast cancer cell surface and by contributing to their downstream signaling pathways (Kufe, 2012). In this regard, the 72 amino acid MUC1-C cytoplasmic domain acts as a substrate for EGFR and other RTKs. The MUC1-C cytoplasmic domain also contains a YHPM motif, that when phosphorylated on tyrosine, functions as a binding site for PI3K SH2 domains and thereby activation of the PI3K→AKT pathway (Raina et al., 2004; Raina et al., 2011). The MUC1-C subunit is, in addition, targeted to the nucleus where it interacts with certain transcription factors (Kufe, 2009). Of relevance to breast cancer, MUC1-C associates with ERα and this interaction is stimulated by 17β-estradiol (E2) (Wei et al., 2006). MUC1-C binds directly to the ERα DNA binding domain and stabilizes ERα by blocking its ubiquitination and degradation. MUC1-C also enhances ERα promoter occupancy, increases recruitment of coactivators and stimulates ERα-mediated transcription (Wei et al., 2006). Notably, tamoxifen has no effect on MUC1-C/ERα complexes and MUC1-C antagonizes the inhibitory effects of tamoxifen on ERα-mediated transcription (Wei et al., 2006). In other studies, a MUC1-C-induced 38-gene set was applied to the analysis of a database obtained from ER+ breast cancer patients treated with tamoxifen and (i) demonstrated a strong association with ER-dependent signaling, and (ii) predicted failure to tamoxifen treatment, as measured by disease-free and overall survival (Pitroda et al., 2009). These findings have supported a potential link between MUC1-C and tamoxifen resistance; however, there has been no direct evidence to date for such an association.